Modified Oligonucleotides for Treatment of Polycystic Kidney Disease

Abstract

Provided herein are methods for the treatment of polycystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.

1 . A compound comprising a modified oligonucleotide consisting of 9 linked nucleosides, wherein the modified oligonucleotide has the following nucleoside pattern in the 5′ to 3′ orientation:
   N S N S N M N F N F N F N M N S N S    
 wherein nucleosides followed by subscript “M” are 2′-O-methyl nucleosides, nucleosides followed by subscript “F” are 2′-fluoro nucleosides, nucleosides followed by subscript “S” are S-cEt nucleosides, and all linkages are phosphorothioate linkages; and 
 wherein the nucleobase sequence of the modified oligonucleotide comprises the nucleobase sequence 5′-CACUUU-3′, wherein each cytosine is independently selected from a non-methylated cytosine and a 5-methylcytosine; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide comprises the nucleobase sequence 5′-GCACUUU-3′, wherein each cytosine is independently selected from a non-methylated cytosine and a 5-methylcytosine. 
     
     
         3 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 5′-AGCACUUUG-3′, wherein each cytosine is selected independently selected from a non-methylated cytosine and a 5-methylcytosine. 
     
     
         4 . The compound of  claim 1 , wherein each cytosine is a non-methylated cytosine. 
     
     
         5 . The compound of  claim 1 , wherein the compound consists of the modified oligonucleotide or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 1 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         7 . A modified oligonucleotide having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The modified oligonucleotide of  claim 7 , which is a pharmaceutically acceptable salt of the structure. 
     
     
         9 . The modified oligonucleotide of  claim 7 , which is a sodium salt of the structure. 
     
     
         10 . A modified oligonucleotide having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable diluent. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the pharmaceutically acceptable diluent is an aqueous solution. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the aqueous solution is a saline solution. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1 , which is a lyophilized composition. 
     
     
         15 . A pharmaceutical composition consisting essentially of a compound of  claim 1  in a saline solution. 
     
     
         16 . A method for inhibiting the activity of one or more members of the miR-17 family in a cell, comprising contacting the cell with a compound of  claim 1 . 
     
     
         17 . A method for inhibiting the activity of one or more members of the miR-17 family in a subject, comprising administering to the subject a pharmaceutical composition of  claim 11 . 
     
     
         18 . The method of  claim 17 , wherein the subject has a disease associated with miR-17.